tbuckley/cabot-search huggingface dataset:
CTNI-15. PILOT STUDY OF HIGH-DOSE PEMETREXED FOR PROGRESSIVE CHORDOMA
Authors: Santosh Kesari, Naveed Wagle, Jose Carrillo, Akanksha Sharma, Minhdan Nguyen, Judy Truong, Jaya Gill, Raffi Nersesian, Natsuko Nomura, Elnaz Rahbarlayegh, Garni Barkhoudarian, Walavan Sivakumar, Daniel Kelly, Howard Krauss, Matias Bustos, Dave Hoon, Lars Anker, Arun Singh, Kamalesh Sankhala, Tiffany Juarez
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Chordomas are ultra-rare tumors of the spine, and no systemic therapy is approved for refractory disease. Pemetrexed is a multitargeted antifolate that inhibits thymidylate synthase (TS) and other enzymes involved in nucleotide biosynthesis. Considering the majority of chordomas do not express TS, we sought to evaluate the therapeutic activity and safety of high-dose pemetrexed. METHODS Adults with previously-treated chordoma were enrolled on an open-label, single-institution, single-arm, pilot clinical trial. Pemetrexed 900 mg/m2 was administered intravenously every 3 weeks, with supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary and exploratory endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in potential tissue and blood-based biomarkers before and after treatment. RESULTS Fifteen patients with chordoma received a median of 15 (range 4-31) doses of pemetrexed. Median PFS was 10.5 months (95% CI 9 months-undetermined) and 6-month PFS was 67%. Out of 14 response-evaluable patients, two (14%) achieved a partial response and ten (71%) demonstrated stable disease. Adverse events were generally mild at grades 1-2, the most common being fatigue, rash, nausea, constipation, diarrhea, mucositis, vomiting, alopecia, pruritus, lower extremity edema, and alanine transaminase increased. One Grade 3 creatinine increase, one Grade 3 lymphopenia, and one Grade 4 lymphopenia occurred and there were no Grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities. Clinical improvement in disease-related symptoms occurred in several patients. Tumor molecular profiling revealed low mutational burden and though not statistically significant, positive TS expression trended negatively with disease progression. Cell-free microRNAs (cfmiRs) were concordantly detected in plasma and tissues and a blood cfmiR signature was identified that distinguished chordoma from health donors. CONCLUSION High-dose pemetrexed is safe and well-tolerated in chordoma patients. A phase II study is in development. (NCT03955042)
CNSC-36. INDOLENT INTRAVASCULAR LARGE B-CELL LYMPHOMA (IVLBCL) ORIGINALLY PRESENTING AS A STROKE MIMIC
Authors: Nynoshka Bassatt Cabrera, Karan Philip, Ruham Alshiekh Nasany
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND IVBCL is a rare subtype of extranodal diffuse large B-cell lymphoma, characterized by the growth of neoplastic cells in blood vessels with no other apparent extravascular mass, making diagnosis a challenge. It usually has an aggressive and fast-paced course; however, there is limited data regarding incidence due to its rarity. CASE A 73 year-old woman presented with progressive gait worsening a year prior to presentation to our institution. Her symptoms then developed to include left-sided hemiparesis with associated headaches, warranting a local emergency department visit. Brain magnetic resonance imaging (MRI) without contrast showed a Flair hyperintense lesion in the right MCA territory with restricted diffusion, assumed to be an ischemic stroke, and she was started on stroke prevention measures. The patient continued to decline, becoming wheelchair-bound and developing short-term memory loss, chronic headaches, and pseudobulbar affect. Repeat brain MRI without contrast five months later showed progression of the Flair hyperintensity to the left hemisphere with restricted diffusion. Brain MRI with contrast followed, revealing subtle enhancement. Vessel imaging was unremarkable, and cerebrospinal fluid (CSF) analysis was normal with negative cytology and flow cytometry, yet elevated beta-2-microglobulin at 3.25 mcg/mL. A year after symptoms onset, the patient presented to our Neuro-Oncology clinic. Repeat Brain MRI with contrast and spectroscopy showed progression on the left-sided lesion with persistent restriction diffusion and enhancement, prompting a biopsy. Pathology confirmed large B cell lymphoma. PET-CT body scan showed no evidence of systematic disease. The patient was treated with Rituximab, Methotrexate, Vincristine, and Procarbazine (RMVP) with complete response demonstrated by complete resolution of the diffusion restriction and symptoms improvement. CONCLUSIONS Although IVLBCL is known for being a fast progressive disease, we present a case of indolent course delaying diagnosis. Unexplained progressive neurological symptoms with restricted diffusion on MRI should prompt consideration for this diagnosis.
EXTH-66. SINGLE-CELL SPATIOTEMPORAL GENOMICS REVEALS CLONAL EVOLUTION AND THERAPEUTIC TARGET IN RECURRENT DISSEMINATED MEDULLOBLASTOMA
Authors: Hailong Liu, Jiankang Li, Ziwei Wang, Fei Liu, Xiaoguang Qiu, Tao Jiang
Journal: Neuro-Oncology (2023)

Abstract Despite the cellular heterogeneity observed in single-cell studies of medulloblastoma, limited knowledge exists regarding the genetic features and spatiotemporal states of specific cell populations following tumor relapse and dissemination, leading to a lack of effective treatment strategies. In this study, we conducted single-cell transcriptomic, chromatin accessibility, and spatial transcriptomic analyses on 15 primary and recurrent Group 3 medulloblastomas, along with two PDX models (including a lung metastasis model). Subsequently, we deconvoluted our findings with our RNA-seq cohort to further validate cell cluster-specific gene expression associated with relapse and its prognostic significance. We analyzed malignant cells, including cancer stem cells (MB-CSCs), proliferating cells, and differentiated cell populations, and examined gene expression features closely associated with clinical prognosis. To elucidate the origin and maturation process of these malignant cells accurately, we compared tumor cell profiles with early human cerebellar cell-types. Furthermore, we described the spatiotemporal transitions from MB-CSCs to terminal states, with a particular emphasis on the extensive spatial heterogeneity within the tumor during the processes of primary, local relapse, and dissemination. Through computational non-negative matrix factorization (cNMF) analysis, we identified a group of tumor cells in recurrent Group 3 medulloblastoma with high cellular plasticity (HCP), demonstrating strong stemness and proliferative capabilities, as well as the ability to differentiate into multiple functional tumor cell subgroups. This cell population exhibited elevated expression of PTPRZ1, which phosphorylates downstream molecules to promote tumor progression. Through single-cell transcriptomic and chromatin accessibility analyses, we validated the expression of PTPRZ1 in human samples, PDX samples, and transgenic mouse samples. In vitro and in vivo inhibition of PTPRZ1 function using small molecule inhibitors effectively suppressed tumor proliferation and metastatic activity. By employing single-cell spatiotemporal genomics, we elucidated the evolutionary states and subclonal events of primary and recurrent medulloblastoma, and identified PTPRZ1 as a target for effectively inhibiting tumor progression.
IMMU-01. IMMUNE PHENOTYPING OF BRAIN METASTASIS PATIENTS IDENTIFIES A DISTINCT DEPLETION AND EXHAUSTION PHENOTYPE OF THE CD4 T CELLS IN BLOOD AND BONE MARROW
Authors: Merle Reetz, Alice Ryba, Sarina Heinemann, Katharina Kolbe, Jessica Stanik, Svenja Zapf, Jens Gempt, Manfred Westphal, Katrin Lamszus, Eva Tolosa, Cecile Maire, Malte Mohme
Journal: Neuro-Oncology (2023)

Abstract Brain metastases are the most rapidly emerging entity in neuro-oncology. Given the decisive role of immunotherapy, the immune crosstalk between the blood circulation and the brain tumor requires deeper investigation, especially in light of recent data showing that T cells might be trapped in the bone marrow during the metastasis process. We analyzed the immune profile in the peripheral blood and in the bone marrow in a cohort of 40 patients with brain metastasis using flow cytometry. Our results show a global decrease in the proportion of CD3+ T cells in the peripheral blood of patients with brain metastases when compared to healthy donors (HD). CD4+ T cells were more affected by the presence of brain metastases than CD8 cells, with a significant decrease in Tregs, Th1 and Th2 helper cell populations. The proportion of naïve CD4 T cells with low expression of CXCR3 and CD127 is decreased in tumor, while a subpopulation of naïve as well as central memory CD4CM with high expression of PD1 is increased in brain metastasis patients compared to HD. Additionally, we noticed an increase in the proportion of B cells in the patient’ blood, together with a decrease in non-classical CD86+ monocytes compared to HD. The NK cell population was also affected with a significant depletion of mature NK CD57+ in the blood of patients with brain metastases. In the bone marrow, we found an increase in the proportion of senescent CD4CM CD57+ in patients with NSCLC brain metastasis, while the proportion of CD4CM CXCR3+ was significantly decreased compared to HD. Taken together, our data show that brain metastases profoundly affect the phenotype and abundance CD4+ T cells in the periphery and bone marrow, thus interfering with the primary T cell population orchestrating the tumor-specific immune response.
BIOM-31. TARGETED DNA SEQUENCING OF RECURRENT GLIOBLASTOMA IDENTIFIES MOLECULAR FACTORS ASSOCIATED WITH CLINICAL OUTCOMES
Authors: Nadeem Al-Adli, William Chen, Jacob Young, Kanish Mirchia, Zain Peeran, Steve Braunstein, Arie Perry, John de Groot, David Raleigh, Joseph Costello, Mitchel Berger, Harish Vasudevan
Journal: Neuro-Oncology (2023)

Abstract PURPOSE The goal of our project was to define the molecular features of recurrent glioblastoma (rGBM) and their prognostic significance. METHODS We retrospectively reviewed 121 consecutive glioblastoma patients who underwent re-resection at a single institution from 2016-2021. Primary treatment in all patients included maximal safe resection followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ). Capture-based targeted DNA sequencing for point mutations and copy number analysis was performed on all re-resection samples. Overall (OS) and progression-free survival (PFS) from re-resection were analyzed with the Kaplan-Meier method and Cox regression analyses. RESULTS Median age at first recurrence was 57 years (range, 27-78) and follow up from re-resection was 11 months. Salvage therapy comprised re-irradiation (n = 52, 43%), temozolomide (TMZ) (n = 39, 32%), lomustine (n = 47, 39%), and/or bevacizumab (n = 22, 18%). Median OS and PFS were 12.1 and 4.4 months, respectively. Median tumor mutation burden (TMB) was 4 mut/Mb (range, 1-650), average unstable microsatellite sites (MSI) were 1.16% (range, 0-20), and MGMT was methylated in 71 (59%) patients. Longer OS was found after postoperative TMZ (19.1 vs. 9.1), KPS &amp;gt; 70 (13.6 vs. 11.1), and/or re-irradiation (12.6 vs. 8.4) (p&amp;lt; .05). On multivariate analysis, TMZ (HR 0.2, 0.079-0.48), re-irradiation (HR 0.27, 0.12-0.58), and mutations in PDGFRA (HR 0.24, 0.067-0.83) or PTEN (HR 2.3, 1.1-4.8) genes were associated with longer OS after re-resection (p&amp;lt; .05). Multivariate predictors of re-irradiation response included MSI &amp;gt;1.16 (HR 0.25, 0.084-0.75), and mutations in PDGFRA (HR 0.04, 0.005-0.33), TERT (HR 0.16, 0.033-0.78), or PIK3R1 (HR 0.18, 0.041-0.8) genes. In the 46 matched primary/recurrent tumors, 40 (87%%) had a change in a mutation and 9 (20%) demonstrated hypermutation, of which 4 (44%) had mismatch repair deficiencies. CONCLUSIONS Our study outlines the molecular factors associated with survival and response to re-irradiation in rGBM as well as, the molecular differences between primary/recurrent samples.
EPCO-31. THE PROGNOSTIC IMPLICATIONS OF THE RELATIVE ABUNDANCE OF DECONVOLVED TUMOR AND NON-TUMORAL SUBPOPULATIONS IN MULTI-REGIONAL BIOPSIES OF HIGH GRADE GLIOMA WITH BULK RNA-SEQ
Authors: Lee Curtin, Kamila Bond, Sebastian Velez, Andrea Hawkins-Daarud, Javier Urcuyo, Gustavo De Leon, Jazlynn Langworthy, Christopher Sereduk, Kyle Singleton, Pamela Jackson, Chandan Krishna, Richard Zimmerman, Devi Patra, Bernard Bendok, Kris Smith, Peter Nakaji, Kliment Donev, Leslie Baxter, Maciej Mrugala, Leland Hu, Nhan Tran, Osama Al-Dalahmah, Peter Canoll, Kristin Swanson
Journal: Neuro-Oncology (2023)

Abstract High-grade glioma continues to have dismal survival owing in part to its intra- and inter-patient heterogeneity. Standard clinical protocol collects tumor samples with the aim of providing or confirming a diagnosis and determining the status of a few key genes (e.g. IDH1, MGMT). However, this protocol is unable to capture the diversity within tumor regions, immune expression or normal cell abundances that play key roles in the development of the disease. To overcome this, during surgery we collect image-localized multi-regional biopsies to characterize this disease heterogeneity. Data collection is ongoing, and we currently have 202 samples from 58 patients with available bulk RNA-Seq. With a single-cell reference dataset from Columbia University, we used CIBERSORTx, a deconvolution method, to predict relative abundances of 7 normal, 6 glioma, and 5 immune cell subpopulations for each sample. We used Cox proportional hazard models with first-order statistics (mean, minimum, maximum) of abundances within patients to determine whether these are prognostic, then used TCGA RNA-Seq data to validate these findings. We found that one glioma proneural subtype was significantly beneficial for patient survival relative to other glioma subtypes across all statistics (and showed significance in TCGA). Proliferative and mesenchymal glioma subtypes also showed significance for one or two of the calculated statistics. Oligodendrocyte progenitor cell abundances were consistently significantly beneficial for patient survival in our cohort, while an increased abundance of abnormal (reactive) astrocytes is associated with poor prognosis. We also ran these analyses within invasive margin and core tumor regions to determine location-specific population abundances associated with patient survival. In conclusion, understanding the in vivo diversity of cellular subpopulations within high grade glioma is important for treatment stratification and patient benefit.
PATH-20. IDH MUTANT ASTROCYTOMAS WITHOUT RECEIVING ADJUVANT TREATMENT DO NOT DEVELOP HYPERMUTATION OR SPECIFIC GENE MUTATION AND MYC, CDKN2A AND PDGFRA ARE INVOLVED IN MALIGNANT TRANSFORMATION
Authors: Kay Ka-Wai Li, Zhi-Feng Shi, Johnny Sheung-Him Kwan, Danny Tat-Ming Chan, Ho-Keung Ng
Journal: Neuro-Oncology (2023)

Abstract It is known that temozolomide treatment induces hypermutation and malignant transformation in IDH-mutant astrocytomas at recurrences and “wait-and-see” after resection is acceptable post-operative management. Although a small number of adjuvant-treatment-naive IDH-mutant low-grade astrocytomas have been embedded in well known series of longitudinal gliomas, little specific information is available about the natural evolution of IDH-mutant astrocytoma without selection pressures of temozolomide and irradiation. We studied 19 patients for tissues from primary and recurrent IDH-mutant 1p19q non-deleted Grade 2 gliomas and where no alkylating therapy or radiation was given between primary tumors and malignantly transformed recurrences (2 patients with multiple recurrences). Mean and median follow-ups were 123.1 and 138.8 months. We performed FISH for amplifications for MYC, PDGFRA, homozygous deletion (HD) for CDKN2A and for Alternative Lengthening for Telomeres (ALT). In the paired tumors from 12 patients, panel sequencing was performed. ATRX, p53, IDH mutations and ALT co-occurred in both primary and recurrent tumors for the same patients. MYC was found in tumors from 5/19 patients, three of which were found in the recurrences but not primary tumors. PDGFRA amplification was seen in tumors from six patients, four only in recurrences. Tumors from 11/19 patients showed either CDKN2A HD, MYC or PDGFRA amplification at recurrences. No hypermutated tumors could be found. Only 131 of a total 255 mutations were acquired in the recurrences. NOTCH1 mutation was found only in tumors from 2 patients. No recurrence-specific mutation was identified. p53 mutations when occurring in the primary tumors were associated with a shorter PFS (p=0.011). No mutation of the mismatch repair genes was found and only one POLE mutation was found. CONCLUSION: IDH-mutant low grade astrocytomas not being treated with temozolomide or irradiation do not develop hypermutation or specific gene mutation for their natural evolution and malignant transformation.
MODL-38. DEFINING THE ROLE OF DAAM2 R414W MUTATION IN GLIOMAGENESIS AND GBM GROWTH
Authors: Tiffany Choy, Qi Ye, Benjamin Deneen, Melissa Bondy, Hyun Kyoung Lee
Journal: Neuro-Oncology (2023)

Abstract Each year in the United States, more than 13,000 people are diagnosed with glioblastoma multiforme (GBM), and more than 10,000 are estimated to succumb to the disease, making GBM the most common and lethal primary adult brain tumor. Despite advancing therapies, GBM patient survival has not improved over the decades, so it is critical to better understand glioma etiology. The majority of GBM cases arise from a sporadic accumulation of somatic mutations, but approximately 5-10% of gliomas are classified as “familial”, occurring clustered with hereditary cancer predispositions. These familial gliomas are caused by germline mutations inherited from parent to offspring, and only a few of these mutations have been directly linked to the development of GBM. We recently discovered five germline mutations in Daam2 (Dishevelled associated activator of morphogenesis 2) from GBM patients with a history of familial glioma. To examine the role of these mutations in GBM, we overexpressed these mutations in patient-derived GBM cells, which were then orthotopically xenografted into immunodeficient mice. We identified that one of these mutations, Daam2-R414W, promotes tumor cell proliferation both in vitro and in vivo. To further understand the role of the Daam2-R414W mutation in GBM, we generated a knock-in immunocompetent mouse model that harbors the Daam2-R414W mutation. In these mutant mice, we found increased proliferation of glial progenitor cells in the subventricular zone compared to Daam2 wildtype mice, suggesting the potential of the Daam2-R414W mutation to influence glial progenitor expansion to stimulate glioma initiation. Future experiments aim to answer whether this mutation promotes GBM growth in an immunocompetent model and to decipher the mechanism relating the Daam2-R414W mutation to GBM pathology. These studies will shed light on the repercussions of a human developmental gene variant and its potential to disrupt normal cellular machinery to promote malignancy and GBM development.
QOL-25. FOR THE LOVE OF WORK: NOVEL STUDY OF VOCATIONAL COGNITIVE REHABILITATION IN PRIMARY BRAIN TUMOR
Authors: Christina Weyer Jamora, Melissa Brie, Paige Bracci, Ellen Smith, Tracy Luks, Stephanie Phan, Steven Braunstein, Nancy Ann Oberheim Bush, Nicholas Butowski, Jennifer Clarke, Mariza Daras, John de Groot, Susan Chang, Jennie Taylor
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Primary brain cancer survivors live longer, yet experience distress and cognitive impairments that negatively impact their quality of life (QOL), including at work. We present a novel study of vocational tele-cognitive rehabilitation in primary brain cancer survivors. METHODS Retrospective review, post-treatment, radiologically stable adult primary brain cancer patients who completed standardized neuropsychological, psychological, vocational, and QOL assessments. Wilcoxon rank sum and Fisher’s exact or Chi-square tests assessed between-group and within-group comparisons. Tests were two-sided and statistically significant for p &amp;lt; 0.05. RESULTS 79 patients with known baseline work status assessed for between-group comparisons (working versus not). Working (n = 38) and not working (n = 41) subgroups had similar ages, tumor grade/type, and history of radiotherapy. Working had worse executive functioning (p = .05). Not working (n = 41) had worse cognitive function (executive function, attention, verbal learning all p &amp;lt; 0.05) and more engagement in survivorship services (p &amp;lt; 0.04). Of the 79 work-status known patients, 38 underwent vocational tele-cognitive rehabilitation (median 11 sessions) treatment for within-group comparisons. 82% of the treatment group had improved work status compared to 34% in non-treatment. Baseline work status and age were not related to occupational improvements (all p &amp;gt;0.20). Higher dose high radiotherapy dose inversely related to rehab improvements (p&amp;lt; .05). Higher verbal memory (p = 0.05), processing speed (p = .06), executive functioning (p = 0.02), IDH mutation status (p = .06), and motivation for treatment (p = .04) was associated with improvement. Those with depressive symptoms who engaged in clinically indicated psychotherapeutic services significantly improved their work status (p = .01). CONCLUSION Occupational functioning improved after cognitive rehabilitation. Cognitive impairments, IDH mutation status, higher dose radiotherapy, and treatment motivation are important. Not working at baseline, despite more cognitive impairments, improved similar to their working counterparts. Those with depression benefitted from psychotherapeutic support. Vocational tele-cognitive rehabilitation shows promise for improving the work-based abilities of primary brain tumor patients and warrants further investigation.